Pancreatic cancer is associated with profound insulin resistance, resulting in diabetes in up to 80% of patients. This metabolic abnormality is tumor dependent and disappears after tumor resection, despite the loss of islets. Amylin is a pancreatic hormone that inhibits muscle glycogen synthesis and reduces food intake. In most pancreatic cancer patients, amylin levels are elevated in the fasting state. Even though diabetes may not be a major problem for the management of patients with pancreatic cancer, measurement of amylin may be a valuable marker for the early diagnosis of the disease, at least in a proportion of patients. Furthermore, the increased amylin levels appear to result from stimulation of peri-tumoral islets by a tumor-derived peptide (amylin releasing peptide of ARP). It is likely that, compared with amylin, circulating ARP levels are elevated in an even higher proportion of pancreatic cancer patients. The major goals of this proposal are as follows: 1. To investigate the specificity of elevated circulating amylin in pancreatic cancer, by investigating patients with pancreatitis, biliary obstruction, newly diagnosed diabetes, pancreatic cancer or other malignancies. 2. To purify and sequence ARP and develop a radioimmunoassay to measure this peptide. 3. To establish whether ARP is a better marker for pancreatic cancer than amylin, by measurement in the above groups of patients. 4. To determine the value of amylin and ARP as early indicators of pancreatic cancer, by measuring the peptides in families with a high risk of developing the disease, and by measuring them in samples from pancreatic cancer patient collected several years prior to their cancer diagnosis. This study may aid in the development of an early screening technique for detecting pancreatic cancer at an early, curable stage. In addition, it will improve our understanding of the role played by the islets in this disease.